[unreadable] Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions that affects individuals throughout their life. Both Crohn's disease (CD) and ulcerative colitis (UD) are thought of as autoimmune diseases, and colonic epithelial cells (CEC) and underlying lamina propria (LP) cells may play a critical role during the development of IBD. However, the exact mechanistic role of these two populations in the pathogenesis, or alternatively in the regulation of IBD, is still unclear. We have previously identified that tumor necrosis factor receptor -type I (TNFR1) and -type II (TNFR2) are expressed by CEC: TNFR1 is constitutively expressed whereas TNFR2 expression is induced under inflammatory conditions. The induction of TNFR2 on CEC is closely associated with colonic proliferation and hyperplasia. Our recent preliminary studies have also identified that the TNFR1 expressed on non-lymphoid, myeloid lineage cells (most likely dendritic cells and macrophages) present in LP cells is a critical regulator of innate immune responses by inducing apoptosis in LP cells. Excitingly, this TNFR1-mediated regulation of innate immune responses contributes to the initiating CEC restitution through the MAPK pathway activation. These discoveries provide us with a great opportunity to more closely examine the role of TNFR1 and TNFR2 in CEC and non-lymphoid LP cells in the pathogenesis of colitis. Based on our preliminary studies, we hypothesize that TNFR1 plays a critical role in the regulation of human IBD. In Aim I, we plan to examine the suppressive role of TNFR1 against TNFR2 mediated signaling cascade on CEC and macrophages: the effect will be examined by using cell lines which TNFR1 and/or TNFR2 are constitutively or artificially overexpressed or knocked-down after ligated with two distinct TNFR ligands, TNF and Lymphotoxin. In Aim II, we will examine the role of Chitinase 3-like-1 (CHI3L1) that may negatively regulate the TNFR1 signalings during the acute and following recovery phase of colitis. The CHI3L1 had been initially picked up by DNA microarray analysis and this molecule may be actively involved in the pathogenesis of IBD. These studies will help clarify the distinct regulatory role of TNFR1-mediated activation of CEC in the type of ligands under intestinal inflammation. We believe the data obtained from this study would provide an important rationale to develop new TNF related therapeutic approaches for human IBD. [unreadable] [unreadable] [unreadable]